7. Project Summary/Abstract Schizophrenia (SZ) is a devastating neuropsychiatric illness with typical onset in early adulthood. Despite extensive research, its causes remain poorly understood. Our central hypothesis is that abnormalities in cell membrane phospholipids, particularly those involving arachidonic acid (AA) and related metabolites (collectively termed eicosanoids) are fundamental to at least one etiopathological pathway involved in SZ. The proposed work will test whether niacin subsensitivity can serve as a putative physiologic marker to identify a subset of individuals at onset of illness for SZ. Although niacin subsensitivity is a widely replicated physiological abnormality associated with SZ, issues of illness chronicity and exposure to antipsychotic medications confound most published data. The proposed research will effectively resolve this issue by studying a large sample of first-episode, drug-nave (FEDN) patients. However, enrollment of such a unique group in the US can be challenging for a single study site. The proposed R21 project will thus be conducted exclusively at the Beijing Hui-Long-Guan Hospital. Because of its enriched resource for this unique patient population, it is not only feasible but also cost-effective to meet the recruitment goal of 300 FEDN patients. The following three specific aims are proposed: Aim 1: Estimate the prevalence of niacin subsensitivity in FEDN patients. We will use a Laser Doppler flowmeter to quantify the cutaneous blood flow response to increasing concentrations of topical -methylnicotinate (AMN) in 300 FEDN psychosis patients, and 100 demographically-balanced healthy controls (HC) from Beijing site. We hypothesize that niacin sensitivity will be significantly reduced in 25% or more of FEDN-SZ subjects, but in fewer than 10% of HC and FEDN with other psychosis. Aim 2: Estimate the extent to which niacin subsensitivity is a stable marker that is predictive of SZ. We will build a classification model using initial niacin sensitivity from 300 FEDN patients (defined as the EC50 value for topical methylnicotinate to stimulate skin blood flow) to predict a diagnosis of SZ at 6-month reassessment. We hypothesize that niacin subsensitivity is a stable trait, and initial niacin sensitivity during early psychosis is predictive of a subsequent diagnosis of SZ. Aim 3: Evaluate the biochemical mechanisms underlying niacin subsensitivity. We will compare niacin sensitivity with likely chemical mediators (phospholipids, arachidonic acid and eicosanoids) from plasma and RBC samples between FEDN patients and HC groups (from Aim 1). We hypothesize that niacin subsensitivity will be associated with defects in the AA cascade. A model for prediction of EC50 values in the same enrolled FEDN and HC groups from Aim 1, will have at least one significant AA predictor after correction for multiple testing. While we do not believe that all patients have defects in AA signaling, the proposed study will establish the validity of an objective physiological marker that could help to identify a subset of SZ patients at a very early stage of illness. Elucidating its biochemical mechanism may lead to refined diagnostic methods and novel targets for drug development.